Subcutaneous analyte sensor

ABSTRACT

Assembly and method for measuring the concentration of an analyte in a biological matrix. The assembly includes an implantable optical-sensing element that comprises a body, and a membrane mounted on the body in a manner such that the membrane and the body define a cavity. The membrane is permeable to the analyte, but is impermeable to background species in the biological matrix. A refractive, element is positioned in the cavity. A light source transmits light of a first intensity onto the refractive element, and a light detector receives light of a second intensity that is reflected from the cavity. A controller device optically coupled to the detector compares the first and second light intensities, and relates the intensities to analyte concentration.

BACKGROUND OF THE INVENTION

The present invention relates to implantable sensors, and morespecifically, to implantable sensors for monitoring levels of analytes,such as glucose.

Several designs for implantable sensors that allow continuous in vivomonitoring of levels of analytes such as glucose have been previouslydescribed. Many such designs are based on electrochemical analytedetection principles. As such, they are prone to inherent signalinstability of the sensor, and they require that chemicals (e.g.,enzymes and mediators) be introduced into the patient's body.

A second approach involves physical (i.e. reagent-free) methodology. Areview of physical methods for determinations of glucose in vivo isgiven in J. D. Kruse-Jarres “Physicochemical Determinations of glucosein vivo,” J. Clin. Chem. Clin. Biochem. 26 (1988), pp. 201-208. Nuclearmagnetic resonance (No), electron spin resonance (ESR), and infrared(IR) spectroscopy are named, among others, as non-invasive methods.However, none of these methods has as yet acquired practicalsignificance. Some of them require large and expensive apparatus,generally unsuitable for routine analysis and home monitoring of apatient.

Nearly all of the methods of this second approach are based onspectroscopic principles. Concerning the optical methods, thefundamental principle frequently is the interaction of the irradiatedprimary light (of a specific wavelength) with the vibration and rotationstates of the molecules undergoing analytical determination. The basicvibrational and rotational states of glucose are found in the IR regionat wavelengths above 2500 nm. This spectral region is not suitable forinvasive analytical determination of glucose because of the strongabsorption of water, which is present in high concentration inbiological matrices. In the near infra-red (NI) region, the absorptionof water is smaller (the so-called “water transmission window). Thespectral analysis of glucose in this region is based on absorption byovertones and combination oscillations of the basic vibrational androtational states of the glucose molecule (see the article byKruse-Jarres cited above and EP-A-0 426 358).

Developing a practical implantable glucose sensor on the basis of theseprinciples presents certain problems. These problems result particularlyfrom the fact that the effective signal (the change in the absorptionspectrum due to a change in glucose concentration) is generally verysmall. Sensitivity is always an issue in absorption measurements becauseof the difficulty in observing a small effective signal superimposed ona relatively much larger background signal. However, in this case thedifficulty is enhanced due to background signals resulting from thespectral absorption of water. Some attempts have been made to solve thisproblem (see e.g., EP-A-0 160 768; U.S. Pat. No. 5,028,787; and WO93/00856); however, these attempts have not been successful in providinga practical and functional implantable glucose sensor based onabsorption principles.

Methods of continuously monitoring glucose based on light scatteringprinciples have also been described. For instance, European patent 0 074428 describes a method and device for the quantitative determination ofglucose by laser light scattering. The method assumes that glucoseparticles scatter light rays transmitted through a test solution, andthat the glucose concentration can be derived from this scattering. Themethod requires measurement of the spatial angular distribution of thetransmitted (i.e. forward-scattered) light emerging from a test cuvetteor an investigated part of the body. In particular, the intensity of thetransmitted light is measured in an angular region in which the changein relation to the glucose concentration is as large as possible. Thisintensity is then compared with the intensity measured for the centralray passing directly through the sample. For in vivo analyticaldetermination, a transmission measurement on ear lobes with laser lightis exclusively recommended.

A second method based on light scattering principles relies on themeasurement of back-scattered light rather than transmitted (i.e.forward-scattered) light. U.S. Pat. No. 5,551,422 describes a method fordetermining glucose concentration in a biological matrix by performingat least two detection measurements. In each detection measurement,primary light is irradiated into the biological matrix through aboundary surface thereof at a defined radiation site. The light ispropagated along a light path within the biological matrix. An intensityof the light is measured as the light emerges as secondary light througha defined detection site of the boundary surface. At least one of thedetection measurements is a spatially resolved measurement of multiplyscattered light. The detection site is located relative to theirradiation site such that light which was multiply scattered atscattering centers in the biological matrix is detected. The light pathsof the at least two detection measurements within the biological matrixare different. Glucose concentration is then derived from the dependenceof the intensity of the secondary light on the relative positions of theirradiation site and the detection site.

Additional methods are needed which minimize or eliminate the effect onlight intensity from variations of physical parameters, such astemperature and/or changes in the concentrations of background ions,proteins, and organic acids in the biological matrices, and whichminimize the number of light paths and/or detection measurementsrequired to be performed.

BRIEF SUMMARY OF THE INVENTION

The present invention, in one form thereof, comprises an assembly formeasuring the concentration of an analyte in a biological matrix. Theassembly includes an implantable optical-sensing element, a source fortransmitting light into the optical-sensing element, and a detector forreceiving light emitted from the optical-sensing element. Asignal-processing and computing element is provided to compare therespective amounts of transmitted and emitted light, and relate theseamounts to the concentration of the analyte in the biological matrix.The implantable optical-sensing element comprises a body and a membranemounted on the body, such that the membrane and the body define acavity. The membrane is substantially permeable to the analyte, andsubstantially impermeable to background species in the biologicalmatrix, such that the analyte is received in the cavity. A refractiveelement for the transmitted light is positioned in the cavity.

The present invention, in another form thereof, comprises an implantableoptical-sensing element suitable for measuring the concentration of ananalyte in a biological matrix. The optical-sensing element comprises abody, and a membrane mounted on the body such that the body and themembrane define a cavity for receiving the analyte. The membrane issubstantially permeable to the analyte, and substantially impermeable tobackground species in the biological matrix, such as large proteins. Arefractive element having a refractive index different from therefractive index of the analyte is disposed in the cavity.

The present invention, in yet another form thereof, comprises anassembly for measuring the concentration of an analyte in a biologicalmatrix. The assembly comprises an implantable optical-sensing elementcomprising a body, and a first semi-permeable membrane mounted on thebody to define a cavity. The first semi-permeable membrane is permeableto the analyte, and impermeable to background species in the biologicalmatrix. A second membrane is mounted on the body remote from the firstmembrane to define a second cavity. A first refractive element isdisposed in the first cavity, and a second refractive element isdisposed in the second cavity. A light source provides light into eachof the first and second cavities toward the respective first and secondrefractive elements, and a light detector receives light from each ofthe first and second cavities. A signal processor and computer areprovided to relate the respective intensities of the provided light andthe received light to the analyte concentration.

The present invention, in still another form thereof, comprises animplantable optical-sensing element suitable for measuring theconcentration of an analyte in a biological matrix. The optical-sensingelement comprises a body and a first semi-permeable membrane mounted onthe body. The first membrane is permeable to the analyte, andimpermeable to background species in the biological matrix. The firstmembrane and the body are aligned to define a first cavity, the firstcavity having a first refractive element disposed therein. A secondmembrane is mounted on the body remote from the first membrane. Thesecond membrane and the body are aligned to define a second cavityisolated from the first cavity, the second cavity having a secondrefractive element disposed therein.

The present invention, in yet another form thereof, comprises a methodfor measuring the concentration of an analyte in a biological matrix. Anoptical-sensing element is implanted in the biological matrix, theoptical-sensing element comprising a body and a semi-permeable membranemounted on the body, the semi-permeable membrane being permeable to theanalyte and impermeable to background species in the matrix. Thesemi-permeable membrane and the body define a cavity, and a refractiveelement is disposed in the cavity. Primary light from a light-emittingsource is introduced into the body of the optical-sensing element, andis directed toward the refractive element. Secondary light reflectedfrom the optical-sensing element is collected and transmitted to alight-detecting device. The intensity of the secondary light ismeasured, and the analyte concentration in the biological matrix isdetermined by comparing the intensity of the secondary light with theintensity of the primary light.

The present invention, in a still further form thereof, comprises amethod for measuring the concentration of an analyte in a biologicalmatrix. An optical-sensing element is implanted in the biologicalmatrix, the optical-sensing element comprising a body, a first membranemounted on the body, and a second membrane mounted on the body remotefrom said first membrane. At least one of the membranes is permeable tothe analyte and impermeable to background species in the biologicalmatrix. The first and second membranes define a cavity, and a refractiveelement is disposed in the cavity. Primary light from a light-emittingsource is transmitted into the cavity toward the refractive element, andsecondary light reflected from the refractive element is collected andtransmitted to a light-detecting device. The intensity of the secondarylight is measured with the light-detecting device, and the analyteconcentration in the biological matrix is derived therefrom.

The present invention, in another form thereof, comprises a method formeasuring the concentration of an analyte in a biological matrix. Anoptical-sensing element is implanted in the biological matrix, theoptical-sensing element comprising a body, a first semi-permeablemembrane mounted on the body, and a second semi-permeable membranemounted on the body remote from the first semi-permeable membrane. Thebody and the first membrane define a cavity having a first refractiveelement disposed therein, and the body and the second membrane define asecond cavity isolated from the first cavity and having a secondrefractive element disposed therein. Primary light from a light-emittingsource is transmitted into the body, and respective streams of theprimary light are directed into the first cavity toward the firstrefractive element, and into the second cavity toward the secondrefractive element. Light reflected from the first refractive element iscollected and transmitted to a first channel of a light-detectingdevice, and light from the body reflected at the second refractiveelement is collected and transmitted to a second channel of thelight-detecting device. The respective intensities of light collectedfrom each of the first and second channels is measured, and theconcentration of an analyte in the biological matrix is computed bycomparing the intensity of the transmitted light and the light collectedfrom each of the first and second channels.

The present invention, in yet another form thereof, comprises anassembly for monitoring the concentration of an analyte in a biologicalmatrix. The assembly includes an implantable optical-sensing elementthat comprises a body, a membrane mounted on the body, and a refractiveelement disposed in a cavity defined by the membrane and the body. Theanalyte is received in the cavity through the membrane, wherein themembrane is substantially permeable to the analyte of interest andsubstantially impermeable to background species in the biologicalmatrix. One or more light sources provide light of a first wavelengthand a second wavelength into the cavity, the refractive element in thecavity having a refractive index greater than the refractive index ofthe analyte at the first wavelength, and less than the refractive indexof the analyte at the second wavelength. A detector receives from thecavity an intensity of light at each of the first and second wavelengthsat a first concentration of said analyte, and receives an intensity oflight at each of the first and second wavelengths at a secondconcentration of the analyte. A signal-processing and computing elementis optically coupled to the detector for comparing the intensities oflight received at the first wavelength to the intensities of lightreceived at the second wavelength, and for relating the intensities toanalyte concentration.

The present invention, and yet another form thereof, comprises a methodfor monitoring a change in the concentration of an analyte in abiological matrix of a test subject. An optical-sensing element isimplanted in the test subject, the implantable optical-sensing elementcomprising a body and a membrane mounted on the body, wherein themembrane and body define a cavity for receiving the analyte. Themembrane is substantially permeable to the analyte of interest andsubstantially impermeable to background species in the biologicalmatrix. A refractive element is disposed in the cavity. Light of a firstwavelength and a second wavelength is introduced into the cavity,wherein the refractive element has a refractive index greater than therefractive index of the analyte at the first wavelength, and less thanthe refractive index of the analyte at the second wavelength. Anintensity of light at each of the first and second wavelengths ismeasured at a first concentration of the analyte, and an intensity oflight at each of said first and second wavelengths is measured at asecond concentration of the analyte. The change in concentration of theanalyte is computed by comparing the intensities of light received atthe first wavelength to the intensities of light received at the secondwavelength for each of the first and second concentrations, and relatingthe intensities to changes in analyte concentration.

BRIEF DESCRIPTION OF THE DRAWINGS

Various other objects, features and attendant advantages of the presentinvention will be more fully appreciated as the same becomes betterunderstood from the following detailed description when considered inconnection with the accompanying drawings in which like referencecharacters designate like or corresponding parts throughout the severalviews and wherein:

FIG. 1 shows a side cross-sectional view through the Y₁Z₁-plane of anoptical-sensing element according to a first embodiment of the presentinvention;

FIG. 2, shows a front cross-sectional view through the X₁Y₁-plane of theoptical-sensing element illustrated in FIG. 1;

FIG. 3 shows a shows a top cross-sectional view through the X₁Z₁-planeof the optical-sensing element illustrated in FIG. 1;

FIG. 4 shows a side cross-sectional view through the Y₂Z₂-plane of anoptical-sensing element according to a second embodiment of the presentinvention;

FIG. 5 shows a front cross-sectional view through the X₂Y₂-plane of theoptical-sensing element illustrated in FIG. 4;

FIG. 6 shows a top cross-sectional view through the X₂Z₂-plane of theoptical-sensing element illustrated in FIG. 4;

FIG. 7 shows a side cross-sectional view through the Y₃Z₃-plane of anoptical-sensing element according to a third embodiment of the presentinvention;

FIG. 8 shows a front cross-sectional view through the X₃Y₃-plane of theoptical-sensing element illustrated in FIG. 7;

FIG. 9 shows a top cross-sectional view through the X₃Z₃-plane of theoptical-sensing element illustrated in FIG. 7;

FIG. 10 shows a side cross-sectional view through the Y₄Z₄-plane of anoptical-sensing element according to a fourth embodiment of the presentinvention;

FIG. 11 shows a top cross-sectional view through the X₄Y₄-plane of theoptical-sensing element illustrated in FIG. 10;

FIG. 12 shows a front cross-sectional view through the X₄Z₄-plane of theoptical-sensing element illustrated in FIG. 10;

FIG. 13 shows a side cross-sectional view through the Y₅Z₅-plane of anoptical-sensing element according to a fifth embodiment of the presentinvention;

FIG. 14 shows a side cross-sectional view through the X₅Y₅-plane of theoptical-sensing element illustrated in FIG. 13;

FIG. 15 shows a top cross-sectional view through the X₅Z₅-plane of theoptical-sensing element illustrated in FIG. 13;

FIG. 16 shows a side cross-sectional view through the Y₆Z₆-plane of anoptical-sensing element according to a sixth embodiment of the presentinvention;

FIG. 17 shows a side cross-sectional view through the X₆Y₆-plane of theoptical-sensing element illustrated in FIG. 16;

FIG. 18 shows a top cross-sectional view through the X₆Z₆-plane of theoptical-sensing element illustrated in FIG. 16;

FIG. 19 shows a side cross-sectional view through the Y₇Z₇-plane of anoptical-sensing element according to a seventh embodiment of the presentinvention;

FIG. 20 shows a side cross-sectional view through the X₇Y₇-plane of theoptical-sensing element illustrated in FIG. 19;

FIG. 21 shows a top cross-sectional view through the X₇Z₇-plane of theoptical-sensing element illustrated in FIG. 19;

FIG. 22 shows a block diagram of the an opto-electronic detection andmeasurement assembly optically coupled to an optical-sensing element ofthe type described in embodiments 1-5;

FIG. 23 shows another block diagram of the an opto-electronic detectionand measurement assembly optically coupled to an optical-sensing elementof the type described in embodiments 1-5; and

FIG. 24 shows a block diagram of an opto-electronic detection andmeasurement assembly optically coupled to an optical-sensing element ofthe type described in embodiments 6-7.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “biological matrix” denotes a body fluid or atissue of a living organism. Biological matrices, to which the inventionrelates, are optically heterogeneous, that is, they contain a largenumber of substances (e.g., salts, proteins, and organic acids) whichcan affect the refractive index.

As used herein, the term “background species” refers to analytes such asions, proteins, and organic acids native to a biological matrix, or tonon-native agents introduced therein, that are capable of undergoing achange of refractive index substantially as a result of (1) adequatevariations in concentration in vivo, and (2) a large specific refractiveindex increment. “Background species” does not refer to the analyte(s)being monitored.

As used herein, the term “refractive element” is used to refer to anelement having a refractive index different from the refractive index ofthe medium to be measured.

As used herein, the term “mMol” denotes the concentration of a substancein units of millimoles per liter.

As used herein, the term “n” denotes the refractive index of asubstance.

The present invention provides an assembly comprising an implantableoptical-sensing element suitable for measuring the concentration of ananalyte in a biological matrix. The function of the optical-sensingelement is to generate changes in light refraction, which changes are afunction of changes in the concentration of the analyte in thebiological matrix. The optical-sensing element includes a membranemounted on a body, such that the membrane and the body define a cavity.The membrane is substantially permeable to the analyte, therebypermitting the analyte to pass through the membrane and into the cavityby means such as diffusion or osmosis, and is substantially impermeableto background species in the biological matrix.

The optical-sensing element of the present invention is stable overextended periods of time, does not require frequent recalibration, anddoes not require signal amplification through enzymatic reactions. Theoptical-sensing element also minimizes or eliminates background drift insuch measurements due to variations in physical parameters such astemperature and/or changes in the concentrations of background ions,proteins, and organic acids that may be present in the biologicalmatrix.

An example of an analyte suitable for monitor utilizing the assembly ofthe present invention is glucose. It is well known that a change inconcentration of an analyte, such as glucose, in a test solution resultsin a change in the refractive index of the solution. For example, therefractive-index increment of an aqueous glucose solution Δn_(m) forvisible wavelengths is Δn_(m)=2.5×10⁻⁵/mMol glucose (see R. C. Weast,ed., CRC Handbook of Chemistry and Physics, 55^(th) ed. (CRC, Cleveland,Ohio 1974), p. D-205), and this relationship is assumed to beapproximately the same over the entire wavelength region underinvestigation. In other words, the refractive index of a solution risesby approximately 2.5×10⁻⁵ for an increase of one mMol in glucoseconcentration.

Unfortunately, direct measurement of the glucose concentration in abiological matrix based on a change in refractive index is impracticalbecause refractive index is not per se glucose specific. As shown inTable 1, the presence of certain background molecules (e.g., organicacids) and ions (e.g., sodium and chloride) commonly found in biologicalmatrices can substantially affect the refractive index of the matrix.TABLE 1 Concentration (mMol) Substrate Plasma Extracellularintracellular Δn_(m)/mMol glucose 5 5 0 2.5E−05 Na⁺ 142 144 10 5.0E−06K⁺ 4 4 160 5.0E−06 Ca²⁺ 5 3 2 5.0E−06 Mg²⁺ 2 2 25 1.3E−05 Cl⁻ 102 114 25.0E−06 HCO₃ ⁻ 26 30 10 5.0E−06 PO₄ ³⁻ 2 2 100 9.0E−06 SO₄ ²⁻ 1 1 201.0E−05 organic acids 5 5 0 6.0E−06(Concentration expressed in % w/v)Independent concentration changes in these species could interfere withthe glucose measurement and result in drift or erroneous readings.

The present invention addresses this problem by providing anoptical-sensing element having a substantially impermeable body that isenclosed on at least one surface thereof by a semi-permeable membrane.The semi-permeable membrane is designed to exclude undesired backgroundmolecules and/or ions from entering/exiting the interior of the body,while allowing the analyte or analytes of interest to freely diffusethrough the membrane. When the analyte of interest is glucose, theglucose diffuses through the membrane to equilibrate with tissue glucoseconcentration. Background species cannot permeate through the membrane.For example, proteins can be excluded by using membranes with adequatepore size (e.g., 30 kD to exclude albumin but enable glucose diffusion),and ions can be excluded by using a polarized membrane (±) layer.

It is preferred to use a bipolar membrane as the semi-permeablemembrane. Bipolar membranes are ion exchange membranes constructed oftwo adjoining layers of ion exchangers of opposite polarity (i.e. acation-exchange side and an anion-exchange side). The charge density ofthese membranes is such that ions of the same charge as the fixedcharges are hindered from diffusing through the membrane. Bipolarmembranes are useful for isolating one ionic environment from another.These membranes are highly hydrated, and are thus permeable tonon-charged solutes, such as glucose, which can diffuse from one side tothe other.

Suitable bipolar membranes for use in the present invention includethose produced by Tokuyama Soda (Japan) under the trade name ofNeoSepta, available from Electrosynthesis Company, Lancaster, N.Y. Thesemembranes are produced for bulk electrolysis and salt-splittingapplications, and thus are mechanically very stable and rigid. Theypossess the high charge densities required for use in the high saltconcentrations of biological matrices. These membranes are approximately250 um in thickness, and may be cut to any appropriate size. Thinnermembranes of lower ionic content could also be used. Thinner membranesare advantageous because they decrease the response time of the sensorand may provide more accurate results.

During use, the semi-permeable membrane must be bonded to the body ofthe optical-sensing element in a manner that prevents infusion ofsolution in or out of the interior of the body except through themembrane. This bonding may be accomplished by any of several methods,including heat or ultrasonic bonding, adhesive bonding withpressure-sensitive adhesives or liquid adhesives such as cyanoacrylates(e.g., Superglue or Crazyglue), thermoplastic adhesives such asurethanes or hot-melt adhesives, or photocurable adhesives. Preferredbonding methods for in vivo applications include chemical or physicalmethods such as heat or ultrasonic bonding.

Typical commercial bipolar membranes comprise a cross-linked polystyrenesulfonate for the cation-exchange side bonded to a crosslinkedpoly(vinyl benzyl trimethyl ammonium chloride) for the anion-exchangeside. The membranes are typically supplied in a high concentration (10%)of salt for stabilization, and are equilibrated with a physiologicalsaline solution (1.15 M NaCl) prior to use in the optical-sensingelement. The bipolar membranes are preferably cross-linked to an extentthat large molecular weight solutes such as proteins and lipids are alsoexcluded from the membrane, and concomitantly, from the volume enclosedby the membrane.

If a thinner bipolar membrane is used to enable a more rapid responsetime, it may be desirable to combine the bipolar membrane with a thirdmembrane layer capable of excluding macrosolutes. Such a third membranelayer may, for example, be any of the membranes typically used fordialysis applications, such as regenerated cellulose or polyamidemembranes. The third membrane layer may be attached to the sensor body,on or around the bipolar membrane, using any of the methods suitable forattaching the bipolar membrane. Alternatively, the third membrane layermay be laminated directly to the bipolar membrane prior to applicationof the bipolar-membrane to the sensor body. Moreover, the third membranelayer may be formed on the bipolar membrane by a casting process, forexample, by dipping the assembled optical-sensing element with bipolarmembrane attached into a solution of a membrane-forming polymer, andthen drying the element under controlled conditions.

Bipolar membranes can be formed into hollow fibers in the same way thatmembranes for dialysis and microdialysis are produced, and themembrane-fibers slid over the sensor structure and attached with any ofthe above methods.

The spectroscopic principle relied upon in the present invention is thatlight is reflected or refracted at changes in refractive index. Thecloser the refractive indices of two interfacing media, the smaller thespecular reflection. When the refractive indices match, no specularreflection is observable. Correspondingly, the specular reflectionincreases in absolute magnitude as the refractive indices of the twointerfacing media become more disparate. However, the relative change inspecular reflection is largest when the refractive index differential issmall, as discussed in M. Kohl, M. Cope, M. Essenpreis, and D. Bbcker,Optics Letters, Vol. 19, No. 24, (1994) pp. 2170-2172, which isincorporated herein by reference in its entirety. Based upon thesecompeting effects, it has been determined that the sensitivity of themeasurement is optimized when the refractive index of a refractiveelement disposed within the body, and the refractive index of an analytesuch as glucose are preferably within 9%, more preferably within 5%, ofeach other when the glucose concentration in the biological matrix is atphysiological levels, i.e., between 4 and 7 mMol.

When the analyte of interest is glucose, the refractive element ispreferably formed from a material with a refractive index close to thatof a glucose solution at physiological concentrations (i.e. n=1.38).Preferably, the refractive element is formed from a moldable plastichaving a refractive index between 1.26 and 1.50, more preferably between1.31 and 1.45. Examples of suitable plastics includepoly(undecafluorohexyl acrylate) (n−1.36), poly(decamethylene carbonate)(n=1.47), poly(ethylene succinate), poly(ethylene oxide) (n=1.46),poly(trifluoroethylene) (n=1.34), poly(hexafluoropropylene) (n=1.31),poly(methyl methacrylate) (n=1.49), poly(ethylene) (n=1.49),poly(oxy(diethylsilylene)) (n=1.42), and poly(vinyl fluoride) (n=1.45).Preferred plastics include poly(methyl methacrylate) and poly(ethylene).

A first embodiment of the optical-sensing element of the invention isillustrated in FIGS. 1-3. The optical-sensing element includes a body100, a semi-permeable membrane 110 and a refractive element 114. Thebody 100 and membrane 110 are oriented to define a cavity 112. Therefractive element 114 and the analyte or analytes of interest (notshown) are disposed in the cavity 112. The semi-permeable membrane 110is substantially permeable to the analyte(s), but substantiallyimpermeable to background species in the biological matrix.

Preferably, the body 100 of the optical-sensing element has a generally“U” or “V”-shaped cross-section, and comprises a molded plastic. Thebody 100 has a base portion 101 and two opposing side walls 103. Each ofthe side walls 103 includes an upper edge 111. The body 100 has aproximal end 102 and a distal end 104, and is preferably less than 2 mmin length. A light-transmitting conduit 106, here a single opticalfiber, is optically coupled to the proximal end 102 of the body. Opticalcoupling between the body and the conduit can be accomplished by anymeans known in the art, such as, for example, using an adhesive tosecure the conduit 106 in an orifice formed in the body 100.

The refractive element 114 preferably is made from the same material asthe body 100 as part of a single plastic molding process. In theembodiment of FIGS. 1-3, the refractive element 114 comprises aplurality of substantially parallel, rectangular plates. The integral,unit-body construction, with bracing by the rectangular plates, givesthe optical-sensing element particular stability. Preferably, eachindividual plate of the refractive element has a thickness less than 10μm. Each plate has two faces 115 which function as refractive orreflective surfaces. The faces 115 may be flat, or alternatively, may betilted or even randomly shaped structures (e.g., FIGS. 7, 10 and 13).Tilted plates may be useful to avoid interferences. When faces such asthose in FIGS. 1-3 are utilized, the faces 115 are oriented such thateach lies in a plane perpendicular to the longitudinal axis of the body100, and the faces 115 on adjacent plates are preferably separated by nomore than 10 μm.

The change in the intensity of light reflected off the refractiveelement may be maximized by using a refractive element 114 having faces115 capable of multiple reflection and/or refraction in accordance withthe Fresnel formulas. This change may be further maximized by optimizingthe refractive index differential between the analyte and the refractiveelement 114. Preferably, the optical-sensing element includes arefractive element having at least one hundred parallel plates 114 withat least two hundred faces 115. Most of the plates and faces have beenomitted from FIG. 1 for clarity. By using multiple faces 115, theintensity of reflected or refracted light corresponding to changes inrefractive index (and therefore to changes in analyte concentration) canbe amplified by a factor of at least 200.

The body 100 of the optical-sensing element provides a support structurefor the optical-sensing element and should correspondingly be rigid orsemi-rigid. Since the sensing element is designed to be implanted inliving tissue, the construction material of the body 100 should also bebio-compatible. The distal end 104 of the body 100 preferably comprisesa light absorbing material 108, although a transparent material mayalternatively be utilized.

The refractive element 114 can comprise a single structure or aplurality of structures. No particular shape is required. Examples ofsingle structures include a porous fiber, a porous rod, a convolutedribbon, and a convoluted fiber. The refractive element may also comprisecombinations of the foregoing. Examples of pluralities of structuresinclude regular or randomly shaped plates, particles, beads and powders,or combinations of the foregoing. Regardless of the particularembodiment, the refractive element preferably provides a plurality ofreflective or refractive faces 115 that interface with the analyte toamplify the reflected light when compared to light reflected from asingle surface.

A second embodiment of the invention is illustrated in FIGS. 4-6. Thebody 200 of the optical-sensing element comprises two parallel,elongated members 203, each having an upper edge 211 and a lower edge213. The body is preferably formed of molded plastic and is dimensionedin similar manner to the embodiment of FIGS. 1-3. The body 200 alsoincludes a proximal end 202 and a distal end 204. A light-transmittingconduit 206, here a single optical fiber, is sealed in an orifice in theproximal end 202. The distal end 204 preferably comprises alight-absorbing material 208. In this embodiment, a first semi-permeablemembrane 210 is attached to the top edges 211 of the elongated members203, and a second semi-permeable membrane 209 is attached to the bottomedges 213 of the elongated members 203.

The elongated members 203 and semi-permeable membranes 209 and 210define a cavity 212. The cavity contains the analyte of interest (notshown) and a refractive element 214. The refractive element comprises aplurality of substantially parallel, rectangular plates, and theelongated members 203 are held together with cross-support from therectangular plates. In other pertinent respects the numbers andorientation of rectangular plates 214 and faces 215 are similar to thoseas described in the previous embodiment.

A third embodiment of the invention is illustrated in FIGS. 7-9. In thisembodiment, the body 300, base portion 301, side walls 303,light-transmitting conduit 306, light-absorbing material 308, membrane310, edges 311, cavity 312, and respective proximal and distal ends 302and 304 are as described in the embodiment of FIGS. 1-3. The refractiveelement 314 comprises a plurality of beads, which provide a plurality ofreflective or refractive surfaces 315. The composition of the beads isnormally not important, as long as they provide suitable reflective orrefractive surfaces. Glass beads, or beads formed from polymers such aspolystyrene, are particularly suitable. The composition, diameter, andnumber of the beads can be varied to achieve a packing arrangement whichprovides optimal amplification of light by multiple reflections off thebead surfaces 315. A similar effect is achieved when refractive powdersare provided in the, cavity in place of the beads.

A fourth embodiment of the invention is illustrated in FIGS. 10-12. Inthis embodiment, the body 400, base portion 401, side walls 403,light-transmitting conduit 406, light-absorbing material 408, membrane410, edges 411, cavity 412, and respective proximal and distal ends 402and 404 are as described in the embodiment of FIGS. 1-3. The refractiveelement 414 comprises a convoluted ribbon or fiber, which provides aplurality of reflective or refractive surfaces 415. The composition,length, width, and thickness of the ribbon 414 can be varied to achievea packing arrangement which gives optimal amplification of light bymultiple reflections off the surfaces 415. The particular composition ofthe ribbon or fiber is normally not important, as long as suitablereflective or refractive surfaces are provided. Glass or plastic ribbonsand fibers are particularly suitable.

A fifth embodiment of the invention is illustrated in FIGS. 13-15. Inthis embodiment, the body 500, base portion 501, side walls 503,light-transmitting conduit 506, light-absorbing material 508, membrane510, edges 511, cavity 512, and respective proximal and distal ends 502and 504 are as described in the embodiment of FIGS. 1-3. The refractiveelement 514 comprises a rod, or fiber, having a plurality of pores 516.The pores 516 provide a plurality of reflective or refractive surfaces515. The rod should have sufficient porosity so that the interior poresare in contact with the analyte. The composition of the rod or fiber, aswell as the porosity, pore size and number of pores can be can be variedto achieve optimal amplification of light by multiple reflections offthe surfaces 515. The particular composition of the rod or fiber isnormally not important, as long as suitable reflective or refractivesurfaces are provided. Glass or plastic rods and fibers are particularlysuitable.

A sixth embodiment of the invention is illustrated in FIGS. 16-18. Thebody 600 includes a cross-beam portion 601 and two opposing side walls603, and has an “

”-shaped cross-section, preferably manufactured by a plastic moldingprocess. Each of the side walls 603 includes an upper edge 611 and alower edge 621. The cross-beam portion 601 is attached to each side wall603 between the upper edge 611 and the lower edge 621. A firstsemi-permeable membrane 610 is attached to each upper edge 611 of theside walls 603, thereby defining a first cavity 612. A firstlight-transmitting conduit 606, here a single optical fiber, is sealedin an orifice in the proximal end 602 of the body 600 adjacent the firstcavity 612. The distal end 604 of the body 600 preferably comprises afirst light-absorbing material 608 adjacent the first cavity 612. Asecond semi-permeable membrane 620 is attached to each lower edge 621 ofthe opposing walls 603 of the body 600, thereby forming a second cavity622 superposed with respect to the first cavity 612. A secondlight-transmitting conduit 616, here a single optical fiber, is sealedin an orifice in the proximal end 602 of the body 600 adjacent thesecond cavity 622. The distal end 604 of the body 600 preferablycomprises a second light-absorbing material 618 adjacent the secondcavity 622. The first and second cavities include first and secondrefractive elements 614, 624. The refractive elements preferably aremade from the same material as the body 600 and comprise a plurality ofsubstantially parallel, rectangular plates as before. The first andsecond light-absorbing materials, 608 and 618 respectively, preferablyhave the same composition. The second semi-permeable membrane 620 mayhave the same composition as its counterpart in the first cavity 612, ora different composition.

A seventh embodiment of the invention is illustrated in FIGS. 19-21. Thebody 700 of the sensing element has a “

” shaped cross-section, preferably manufactured by a plastic moldingprocess. The body has a base portion 701 and three opposing side walls703. Each of the side walls 703 includes an upper edge 711 a-711 c. Thebody 700 has a proximal end 702 and a distal end 704, and is preferablyless than 2 mm in length. A first semi-permeable membrane 710 isattached to the upper edge 711 a of one of the outer side walls 703 andto the upper edge 711 b of the inner side wall 703, thereby defining afirst cavity 712. A first light-transmitting conduit 706, here a singleoptical fiber, is sealed in an orifice in the proximal end 702 of thebody 700 adjacent the first cavity 712. The distal end 704 of the body700 preferably comprises a first light-absorbing material 708 adjacentthe first cavity 712. The first cavity 712 contains a first refractiveelement 714. The first refractive element 714 is preferably made fromthe same material as the body 700, and comprises a plurality ofsubstantially parallel, rectangular plates.

A second semi-permeable membrane 720 is attached to the upper edge 711 cof the other outer side wall 703 and to the upper edge 711 b of theinner side wall 703, thereby forming a second cavity 722. The secondcavity 722 is in side-by-side orientation with respect to the firstcavity 712. A second light-transmitting conduit 716, here a singleoptical fiber, is sealed in an orifice in the proximal end 702 of thebody 700 adjacent the second cavity 722. The distal end 704 of the body700 preferably comprises a second light-absorbing material 718 adjacentthe second cavity 722. The second cavity 722 contains a secondrefractive element 724. The second refractive element 724 is preferablymade from the same material as the body 700, and comprises a pluralityof substantially parallel, rectangular plates. The first and secondlight-absorbing materials, 708 and 718 respectively, preferably have thesame composition. The second semi-permeable membrane 720 mayindependently have the same composition as its counterpart in the firstcavity 712, or a different composition.

The sixth and seventh embodiments of this invention are particularlyuseful for simultaneously measuring the concentration of two differentanalytes in a biological matrix. This may be accomplished by choosingrespective semi-permeable membranes that are permeable to differentspecies. For example, the first semi-permeable membrane could bepermeable to analyte A but impermeable to analyte B, while the secondsemi-permeable membrane could be permeable to analyte B but impermeableto analyte A. The first cavity would then be used to monitor theconcentration of analyte A, while the second cavity would be used tomonitor the concentration of analyte B.

The sixth and seventh embodiments of this invention may also be usefulfor correcting for background changes in the refractive index of abiological matrix resulting from variations in physical parameters liketemperature. For example, the first semi-permeable membrane could bepermeable to only analyte A, while the second semi-permeable membranecould be impermeable to all of the components (analytes) of thebiological matrix. The first cavity would then constitute a sample cell,while the second cavity would constitute a reference cell. The samplecell could be used to monitor changes in light resulting from changes inthe concentration of analyte A and physical changes in the environmentof the sensing element. The reference cell could be used to monitorchanges in light intensity resulting solely from physical changes in theenvironment of the biological matrix. The differences in light intensitybetween the sample and reference cells would then correlate to thechange in refractive index of the biological matrix due solely to achange in concentration of analyte A.

Alternatively, the first semi-permeable membrane could be permeable toanalyte A and background species in the biological matrix, while thesecond semi-permeable membrane could be permeable to the backgroundspecies but impermeable to analyte A. The first cavity would stillconstitute a sample cell, while the second cavity would constitute areference cell. However, the sample cell would now be used to monitorchanges in light intensity resulting from changes in the concentrationof analyte A, physical changes in the environment of the sensingelement, and changes in the concentration of the background species.Similarly, the reference cell would be used to monitor changes in lightintensity resulting from physical changes in the environment of thesensing element and changes in the concentration of the backgroundspecies. The difference in light intensity between the sample andreference cells would correlate with the change in refractive index ofthe biological matrix due to a change in concentration of analyte A.

The implantable analyte sensor of the present invention is designed tooptically couple with an opto-electronic detection and measurementassembly. The opto-electronic detection and measurement assembly mayinclude the light source for transmitting light from the light source tothe sensing element, or alternatively, the light source may comprise aseparate assembly. The opto-electronic detection and measurementassembly includes a detector for receiving light that has been returnedor otherwise reflected from the sensing element. A signal-processing andcomputing element is optically coupled to the detector to compare theintensity of the received light to that of the transmitted light. Byusing previously measured reference values, the signal-processing andcomputing element converts the differences in light intensity to asignal relating to analyte concentration. The signal can then bedisplayed on a readout device.

The method does not require spectroscopic measurement at one or moredefined wavelengths, although in certain cases it might be advantageousto use multiple wavelengths. When measurement at multiple definedwavelengths is not desired, relatively inexpensive opto-electroniccomponents, such as light emitting diodes (LED's), laser diodes, xenonand metal halide lamps, can be used as the light source.

A block diagram of an opto-electronic detection and measurement assemblyoptically coupled to an optical-sensing element of the type described inembodiments 1-5 is shown in FIG. 22. The first end 802 of a firstlight-transmitting conduit 800 is optically coupled to the proximal end806 of the body of the optical-sensing element 808, for example bysealing the end 802 in an orifice using an adhesive. The second end 804of the first light-transmitting conduit 800 is optically coupled to botha light-emitting source and a light-detecting device. In this diagram,optical coupling is provided by a beam-splitter 810. The beam-splitteris preferably tilted such that the angle of incoming light is equal tothe angle of reflected light, and is oriented such that secondary lightemitted from the second end 804 of the first light-emitting conduit 800is directed into a second light-transmitting conduit 814 connected to alight-detecting device. The light-detecting device can be, for example,a photomultiplier tube or a photodiode. The beam-splitter 810 is alsooriented such that primary light emitted from a third light-transmittingconduit 812 connected to the light-emitting source is directed into thesecond end 804 of the light-transmitting conduit 800. The source canemit light either continuously or in a pulsed mode. Suitable lightsources and detectors can be purchased from Hamamatsu Corporation,Bridgewater N.J. The light-detecting device is electrically coupled to asignal-processing and computing element which converts the secondarylight to an electronic signal that can be read in conventional fashion,such as by visual display on a conventional readout device. Thesignal-processing and computing element may comprise, for example, aconventional controller such as a software-driven computer.

Preferably, each of the first, second, and third light-transmittingconduits, 800, 814, and 812 respectively, comprises one or more opticalfibers. Suitable optical fibers and optical fiber bundles can bepurchased from Polymicro Technologies, LLC of Phoenix, Ariz. Suitablebeamsplitters for optical fibers can be purchased from Oz Optics LTD. ofCarp, Ontario, Canada.

Another block diagram of an opto-electronic detection and measurementassembly optically coupled to an optical-sensing element of the typedescribed in embodiments 1-5 is shown in FIG. 23. In this arrangement,primary light is emitted from a light-emitting source. Thelight-emitting source is optically coupled to the first end 902 of afirst light-transmitting conduit 900, for example using a standard SMAconnector. The second end 904 of the first light-transmitting conduit900 is optically coupled to the proximal end 906 of the body of theoptical-sensing element, for example, by sealing the end 904 in anorifice in the body of the sensing element. The alignment should be suchthat the primary light is directed into the cavity toward the refractiveelement. Secondary light resulting from reflection or refraction at therefractive element is collected in the first end 912 of a secondlight-transmitting conduit 910, which is optically coupled to theproximal end 906 of the body of the optical-sensing element. The secondend of the conduit 914 is optically coupled to a light-detecting device,for example using an SMA connector. The light-detecting device can be,for example, a photomultiplier tube or a photodiode. Preferably, each ofthe first and second light-transmitting conduits, 900 and 910respectively, comprises one or more optical fibers. The light-detectingdevice is electrically coupled to a signal-processing and computingelement, which converts the secondary light to an electronic signal,which can be displayed on a readout device.

A block diagram of an opto-electronic detection and measurement assemblyoptically coupled to an optical-sensing element of the type described inembodiments 6-7 is shown in FIG. 24. Primary light is emitted from alight-emitting source. The light-emitting source is optically coupled tothe first end 922 of a first light-transmitting conduit 920. The secondend 924 of the first light-transmitting conduit 920 is optically coupledto the proximal end 926 of the body of the optical-sensing elementadjacent the first cavity, in an alignment such that the primary lightis directed into the first cavity toward the first refractive element.Secondary light resulting from reflection or refraction at the firstrefractive element is collected in the first end 942 of a secondlight-transmitting conduit 940. The first end 942 of the secondlight-transmitting conduit 940 is optically coupled to the proximal end926 of the body of the optical-sensing element adjacent the firstcavity, while the second end 944 is optically coupled to a channel of alight-detecting device. The light-detecting device can be, for example,a photomultiplier tube or a photodiode.

In addition, the light-emitting source is optically coupled to the firstend 932 of a third light-transmitting conduit 930. The second end 934 ofthe third light-transmitting conduit 930 is optically coupled to theproximal end 926 of the body of the optical-sensing element adjacent thesecond cavity, in an alignment such that the primary light is directedinto the second cavity toward the second refractive element. Secondarylight resulting from reflection or refraction at the second refractiveelement is collected in the first end 952 of a fourth light-transmittingconduit 950. The first end 952 of the fourth light-transmitting conduit950 is optically coupled to the proximal end 926 of the body of theoptical-sensing element adjacent the second cavity, while the second end954 of the fourth light-transmitting conduit 950 is optically coupled toa second channel of the light-detecting device. Preferably, each of thefirst, second, third and fourth light-transmitting conduits, 920, 940,930, and 950 respectively, comprises one or more optical fibers. Thelight-detecting device is electrically coupled to a signal-processingand computing element, which converts the secondary light to anelectronic signal, which can be displayed on a readout device.

The invention further contemplates a method of measuring theconcentration of an analyte in a biological matrix. First, anoptical-sensing element is inserted in the matrix. The optical-sensingelement includes a body, a semi-permeable membrane and a refractiveelement as described previously. Next, primary light is transmitted froma light-emitting source to the body of the optical-sensing element, anddirected into the cavity to the refractive element. Then, secondarylight resulting from the reflection or refraction of the light at therefractive element is collected and read by a light-detecting device.The difference in intensity between the transmitted light and thereflected light is measured by a standard computing device, and theanalyte concentration in the biological matrix is determined by thecomputing device using, for example, an algorithm and calibrationprocedure. Such evaluation algorithms and calibration procedures arewell known to those of ordinary skill in the art.

Once the analyte concentration in the biological matrix has beenderived, the measurement process can be repeated, thereby allowing forcontinuous monitoring of the analyte concentration. Alternatively, themeasurement can be made at specific or random intervals in time. Ineither case, the results can be displayed using means known to those ofordinary skill in the art. For instance, a running graph/chart of theanalyte concentration can be displayed on a monitor. Alternatively, theanalyte concentration can be displayed on a digital readout device or ananalog gauge. Moreover, the electronic signal can be used to trigger analarm on an audio device when the analyte concentration is outside agiven range.

It is a characteristic of the invention that changes in light intensityreturned from the optical sensing component can be related to changes inthe concentration of a specified analyte, such as glucose, in thebiological matrix without the necessity of spectroscopic measurement atmultiple wavelengths. In addition, there is no requirement that twodetection measurements be made, wherein at least one of the detectionmeasurements is a spatially resolved measurement of multiply reflectedlight. All measurements of light intensity returned from the opticalsensing component can be made at the same spatial location. In addition,the principle relied on is light reflection, not optical absorption.Thus, in contrast to previously know spectroscopic methods (particularlyNR spectroscopy), the wavelength is preferably chosen in a region of thespectrum where absorption of the analyte is relatively low.

Spectral regions where the absorption of glucose is relatively low aredescribed, for example, in U.S. Pat. No. 5,551,422. Preferably, thewavelength is between 400 nm and 1300 nm. Other wavelengths outside ofthis range may be utilized in suitable cases, provided that interferingspecies are not substantially present in the matrix, or if present, arecompensated for by the use of proper reference test samples.

In contrast to prior techniques, these spectral regions need notnormally be further narrowed to avoid interferences due to absorption byother components in the biological matrix (e.g., hemoglobin), since thesemi-permeable membrane excludes such components from the sensingvolume. Likewise, there is no particular preference for relatively shortwavelengths because the method does not depend on the depth ofpenetration of light into the biological matrix.

In contrast to absorption-based methods for noninvasive analyticaldetermination of the glucose concentration in a biological matrix, inthe present invention it is generally not necessary to use narrow-bandmeasurement, due to the minimal dependence on the measurementwavelength. Thus, relatively broad-banded light sources (withhalf-widths larger than 20 nm), such as light-emitting diodes (LED's)and other semi-conductor light sources, can be used without the need forsubsequent spectral selection on the primary side or secondary side.This considerably reduces the cost of the apparatus. This feature makesthe apparatus especially suitable for the continuous monitoring of theglucose concentration of a diabetic. Even though it is generally notnecessary to use a laser as a primary light source, in some situations,such as with planar refractive surfaces, laser light may be utilized ifdesired. Similarly, it is generally not necessary to use coherent orpolarized light.

An alternative arrangement to that described above utilizes one or morelight sources that emit light into the cavity at defined wavelengths inorder to exploit the dispersion (i.e., wavelength-dependence) of therefractive indices of the refractive material and/or the analyte. Inthis arrangement, a light source emits light having a wavelength λ₁ atwhich the refractive index of the refractive element n_(element) isalways greater than the refractive index of the analyte n_(analyte).Another light source emits light having a wavelength λ₂ at which therefractive index of the refractive element n_(element) is always lessthan the refractive index of the n_(analyte). The relative index ofrefraction n_(re1)=n_(analyte)/n_(element) at each wavelength is asfollows:n_(re1)=1 for λ₁, andn_(re1)>1 for λ₂.Alternatively, a single light source that emits light at multiplewavelengths may be used in combination with a (dichroic) beam splitterto split the light into separate beams at the desired wavelengths.

When the concentration of the analyte changes, for example increases,n_(analyte) increases and therefore n_(re1) increases for both λ₁ andλ₂. In this setting the relative change in the signals caused by λ₁ andλ₂ is being measured. A relative measurement does not rely on anabsolute calibration and is less affected by background considerations.Hence this arrangement can be used to improve the sensitivity and/or thespecificity of the method.

In implementation of this arrangement using multiple wavelengths, eithera single detector or multiple detectors can be used. For example, whentwo wavelengths λ₁ and λ₂ are used as described above, two separatedetectors can be utilized to receive the signals. One detector wouldreceive the “λ₁-light” and the other would receive the “λ₂-light”. Ifdesired, a wavelength-dependent dicroic beam splitter can be used toisolate the proper wavelength from the reflected light. A controllercould then be utilized to analyze the signals by means such as signalsubtraction to yield an analyte-dependent result. A single detector mayalso be utilized, however in this instance, the signals are generallyreceived alternating in time.

Suitable light sources for use in this multiple wavelength approachinclude multiple independent single light sources each having adifferent wavelength. Alternatively, a beam splitter may be utilizedwith a single, multichromatic light source to split the light intoseparate beams at different, well-defined wavelengths.

The sensor could be designed as a transcutaneous sensor, which uses alight guide to transmit light to: and from the optical-sensing element.Alternatively, the sensor could be an integrated device. In this case,the implanted device would incorporate the light-emitting andoptical-sensing elements in a single element. A fully compatible sensorunit can also include RF data transmission means and a battery charge.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

1-32. (canceled)
 33. An implantable optical-sensing element suitable formeasuring the concentration of an analyte in a biological matrix, saidoptical-sensing element comprising: a body; a membrane mounted on saidbody such that said body and said membrane define a cavity for receivingsaid analyte, said membrane being substantially permeable to saidanalyte, and substantially impermeable to background species in saidbiological matrix; and a refractive-element disposed in said cavity,said refractive element having a refractive index different from arefractive index of said analyte.
 34. The optical-sensing element ofclaim 33, wherein said body comprises two parallel, elongated members,and said refractive element comprises a plurality of plates, each platehaving two faces, said plates being sequentially arranged between saidelongated members and oriented generally perpendicular to said elongatedmembers.
 35. The optical-sensing element of claim 34, wherein saidplates are integral with said elongated members in a unit-bodyconstruction.
 36. The optical-sensing element of claim 33, wherein saidmembrane comprises a first membrane, said optical-sensing elementfurther comprising a second membrane mounted on said body remote fromsaid first membrane.
 37. The optical-sensing element of claim 33,wherein said refractive element comprises at least one of plates,particles, beads and powders.
 38. The optical-sensing element of claim33, wherein said refractive element comprises at least one of a porousfiber, a porous rod, a convoluted ribbon, and a convoluted fiber. 39.The optical-sensing element of claim 33, wherein the refractive elementhas a refractive index within ±9% of the refractive index of saidanalyte.
 40. The optical-sensing element of claim 39, wherein therefractive index of said refractive element is within ±5% of therefractive index of said analyte.
 41. The optical sensing-element ofclaim 33, wherein the refractive element has a refractive index between1.31 and 1.45.
 42. The optical-sensing element of claim 33, wherein saidrefractive element comprises a moldable plastic.
 43. The optical-sensingelement of claim 42, wherein said moldable plastic ispoly(undecafluorohexyl acrylate), poly(decamethylene carbonate),poly(ethylene succinate), poly(ethylene oxide), poly(trifluoroethylene),poly(hexafluoropropylene), poly(methyl methacrylate), poly(ethylene),poly(oxy(diethylsilylene)), or poly(vinyl fluoride).
 44. Theoptical-sensing element of claim 42, wherein said moldable plastic ispoly(methyl methacrylate) or poly(ethylene).
 45. The optical-sensingelement of claim 33, wherein said membrane comprises a bipolar membranehaving a cation-exchange layer and an anion-exchange layer.
 46. Theoptical-sensing element of claim 45, wherein said cation-exchange layerand said anion-exchange layer are bonded together, said cation-exchangelayer comprising a cross-linked polystyrene sulfonate and saidanion-exchange layer comprising a cross-linked poly(vinyl benzyltrimethyl ammonium chloride).
 47. The optical-sensing element of claim46, wherein said membrane further comprises a third membrane layerbonded to one of said cation and anion-exchange layers, said thirdmembrane layer capable of excluding macrosolutes.
 48. Theoptical-sensing element of claim 47, wherein said third membrane layeris a regenerated cellulose or polyamide membrane.
 49. Theoptical-sensing element claim 33, wherein said body includes a proximalend and a distal end, said distal end of said body comprising alight-absorbing material.
 50. The optical-sensing element of claim 33,wherein said body includes a proximal end and a distal end, said distalend of said body comprising a transparent material.
 51. Theoptical-sensing element of claim 33, wherein said body comprises amoldable plastic.
 52. The optical-sensing element of claim 51, whereinsaid body has a “U”-shaped or “V”-shaped cross section.